Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation.
Child
Chromatin
/ chemistry
Enhancer Elements, Genetic
Female
GATA3 Transcription Factor
/ genetics
Genetic Predisposition to Disease
Genome, Human
Humans
Janus Kinases
/ metabolism
Male
Oncogenes
Philadelphia Chromosome
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Protein Binding
Receptors, Cytokine
/ genetics
STAT Transcription Factors
/ metabolism
Signal Transduction
Up-Regulation
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
20
03
2020
accepted:
29
11
2021
pubmed:
5
2
2022
medline:
26
2
2022
entrez:
4
2
2022
Statut:
ppublish
Résumé
Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR-Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK-STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.
Identifiants
pubmed: 35115686
doi: 10.1038/s41588-021-00993-x
pii: 10.1038/s41588-021-00993-x
pmc: PMC9794680
mid: NIHMS1853771
doi:
Substances chimiques
CRLF2 protein, human
0
Chromatin
0
GATA3 Transcription Factor
0
GATA3 protein, human
0
Receptors, Cytokine
0
STAT Transcription Factors
0
Janus Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
170-179Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG009906
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200060
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA098543
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24 DK106766
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124820
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA098413
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA114766
Pays : United States
Organisme : NIGMS NIH HHS
ID : U01 GM092666
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM115279
Pays : United States
Organisme : NIGMS NIH HHS
ID : U01 GM097119
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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